TCDD-mediated suppression of the in vitro anti-sheep erythrocyte IgM antibody forming cell response is reversed by interferon-gamma.
Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established to require the aryl hydrocarbon receptor; however, the downstream mechanisms for this immunotoxic response remain poorly understood. Based on evidence demonstrating that primary hepatocytes pretreated with interferon-gamma (IFN-gamma) exhibited decreased induction of cytochrome P450 1A1 (CYP1A1) by TCDD, and that serum factors alter the sensitivity of the in vitro T-cell-dependent IgM antibody forming cell (AFC) response, it was hypothesized that IFN-gamma attenuates suppression of humoral immune responses by TCDD. In fact, concomitant addition of IFN-gamma (100 U/ml) produced a concentration-related attenuation of TCDD-mediated suppression of the anti-sheep erythrocyte (anti-sRBC) IgM AFC response. Time-of-addition studies performed by adding 100 U/ml IFN-gamma at 0, 1, 2, 4, 12, 24, 48, and 72 h post-TCDD showed that suppression of the AFC response was prevented only when IFN-gamma was added within 2 h of TCDD treatment. mRNA levels of the IgM components, immunoglobulin kappa light chain, immunoglobulin mu heavy chain, and immunoglobulin J-chain were significantly decreased by TCDD treatment, an effect that was completely reversed by IFN-gamma (100 U/ml) cotreatment. Further studies showed that IFN-alpha, IFN-beta, and IFN-gamma significantly attenuate TCDD-induced increases in CYP1A1 mRNA levels to varying degrees, but concentrations as high as 1000 U/ml of type I IFNs did not reverse the effect of TCDD on the anti-sRBC IgM AFC response. In summary, IFN-gamma prevents TCDD-mediated suppression of the IgM AFC response in a concentration- and time-related manner by altering transcriptional effects associated with TCDD treatment.
North
Colin M
CM
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Kim
Byung-Sam
BS
Snyder
Neil
N
Crawford
Robert B
RB
Holsapple
Michael P
MP
Kaminski
Norbert E
NE
D000704:Analysis of Variance; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism; D000917:Antibody Formation / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012756:Sheep; D013154:Spleen / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D000072317:Polychlorinated Dibenzodioxins; C044203:anti-IgM; D007371:Interferon-gamma; D007372:Interferons; D019363:Cytochrome P-450 CYP1A1